ES2208167T3 - PROCEDURE FOR THE PREPARATION OF N- (5-DIFENYL-PHOSPHINOYLMETHYL) -4- (4-FLUOROPHENYL) -6-ISOPROPILPIRIMIDIN-2-IL) -N-METHYLMETHANE-SULFONAMIDE. - Google Patents

Abstract

Procedure for the preparation of N- [5- (di-phenyl-phosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide of the ** formula ** characterized in that it is reacted [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl] methanol of the formula with chlorodiphenylphosphine.

Description

Procedure for the preparation of N- [5- (diphenyl-phosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethane-sulfonamide.

The present invention relates to a procedure for the preparation of N- [5- (diphenyl-phosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethane-sulfonamide of the formula

one

N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide (I), which
It can be prepared according to the invention, it is an intermediate product for the preparation of pharmaceutically active ingredients, for example of HMG-Co A reductase inhibitors (Bioorg. Med. Che. 1997, 5, 437).

The mission of the invention was to find improved access to the intermediate product mentioned above.

The problem could be solved with the new method according to claim 1.

According to the invention the preparation of the N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide of the formula (I) is carried out by reaction of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) -pyrimidin-5-yl] methanol of the formula (II)

two

with chlorodiphenylphosphine

An important advantage of the agreement synthesis With the invention is its large-scale availability.

The [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidin-5-yl] methanol of the formula (II) is easily accessible by reducing the corresponding ester with, p. eg hydride of di-isobutylamino (document EP-A-0521471).

The reaction of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidin-5-yl] methanol of the formula (II) with chlorodiphenylphosphine can be carried out well directly or through prior deprotonization. It preferred direct reaction with chlorodiphenylphosphine, with subsequent base treatment.

According to the "deprotonization" variant mix the [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-ami- no) pyrimidin-5-yl] methanol of formula (II) conveniently with an agent Deprotonizer usual in the technical sector, advantageously with an alkali hydride or an alkaline hexaalkyldisilazane. Is used preferably sodium hydride.

Usually, deprotonization is performed at ambient temperature After this the reaction is carried out with chlorodiphenylphosphine The reaction with chlorodiphenylphosphine is carried out conveniently at a temperature between 80 ° C and 200 ° C.

Chlorodiphenylphosphine can act directly as a solvent However, it is possible to additionally use a inert boiling point solvent as high as possible, as p. ex. toluene or xylene or decalin, as well as corresponding mixtures of isomers.

The reaction may occur in the presence of a catalyst. Iodine, iodides are suitable as catalyst alkalis such as, e.g. e.g., sodium or potassium iodide, alkyl halides such as, e.g. e.g., methyl or iodide ethyl, or dihalogenated alkanes such as, e.g. eg the dibromomethane An alkaline iodide is preferably used. The amount of catalyst is usually chosen in the range of 1% in mol to 20% in moles, based on the alcohol used by the formula II

The reaction according to the direct variant takes place conveniently at a temperature of -20ºC to 130ºC, preferably from + 20 ° C to 120 ° C.

Chlorodiphenylphosphine can, depending on the variant "deprotonization", act directly as a solvent. Do not However, it is possible to additionally use an inert solvent of boiling point as high as possible, such as p. ex. toluno or xylene or decalin, as well as the corresponding mixtures of isomers

Following the reaction with Chlorodiphenylphosphine combines the reaction mixture with a base. Alkaline hydroxides or carbonates are appropriate bases alkalis such as, e.g. eg, an aqueous hydroxide solution sodium or potassium, or sodium or potassium carbonate.

Eventually, to speed up the reaction with the base can be used a usual transfer catalytic phases such as, e.g. eg, a tetraalkylammonium halide. I know they can also achieve good results by applying crown ethers

The N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide of the formula I can be isolated, once the reaction is over, from way known to technical staff, p. ex. by extraction with an appropriate solvent of the reaction mixture, as well as by crystallization in the mixture.

Examples Example 1 N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-iso-propylpyrimidin-2-yl] -N-methylmethanesulfonamide

They were placed in 5 ml of cis / trans-decalin 1.00 g (2.83 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) -pyrimidin-5-yl] methanol and mixed with 204 mg (4.68 mmol) of sodium hydride (55% dispersion in mineral oil). After 30 min at room temperature was added under vigorous stirring for 6 min 680 mg (2.93 mmol) of chlorodiphenylphosphine It was mixed with 52.2 mg (0.35 millimoles) of sodium iodide and heated for 2 h 15 min until 184-186 ° C. After cooling to temperature ambient was mixed with 50 ml of solution 38-40% sodium hydrogen sulphite and 50 ml of ethyl acetate. The organic phase and the phase were separated Aqueous was extracted with 50 ml of ethyl acetate. Phases The combined organics were dried over magnesium sulfate and concentrated under vacuum 1.74 g of crude product were obtained and purified. by chromatography through silica gel (eluent: n-hexane / ethyl acetate 1: 2). 382.4 were obtained mg (25.1%) of N- [5- (diphenylphosphino-ylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-me-tilmethanesulfonamide in the form of a colorless solid. (Melting point 184-185 ° C).

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1 H NMR (DMSO-d 6, 400 MHz): δ = 1.11 (d, J = 6.6 Hz, 6J); 3.28 (Sept, J = 6.6 Hz, 1 HOUR); 3.40 (s, 3H); 3.51 (s, 3H); 4.05 (d, J = 12.6 Hz, 2H); 7.07 (t, J = 8.9 Hz, 2H); 7.35 (m, 2H); 7.42 (m, 4H); 7.5 - 7.9 (m, 6H). 13 C NMR (DMSO-d 6, 100 MHz): δ = 21.52 (q); 29.12 (td); 31.94 (d); 33.07 (q); 41.53 (q); 114.50 (sd); 115.03 (dd); 128.54 (dd); 130.21 (dd); 130.84 (dd); 131.64 (dd); 133.41 (sd); 134.51 (sd); 156.54 (sd); 162.10 (sd); 165.86 (sd); 176.49 (sd).

Example 2 N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-iso-propylpyrimidin-2-yl] -N-methylmethanesulfonamide

They were placed in 4.5 ml of xylene (mixture of isomers) 282.8 mg (0.80 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidin-5-yl] methanol and mixed with 55 mg (1.30 mmol) of sodium hydride (55% dispersion in mineral oil). After 35 min it added at room temperature, under vigorous stirring, for 5  min 185 mg (0.84 mmol) of chlorodiphenylphosphine in 1.5 ml of xylene and then heated for 20 h at 135 ° C. After cooling to room temperature, it was mixed with 15 ml of water and extracted with 10 ml of ethyl acetate. The phase The organic was separated and the aqueous phase was extracted with 2 x 10 ml of ethyl acetate. The organic phases were dried pooled (MgSO4) and concentrated in vacuo. 510 mg were obtained of crude product, which was purified by gel chromatography of silica (eluent: n-hexane / ethyl acetate 1: 2, then ethyl acetate) and 230 mg (53.5%) of N- [5- (diphenyl-phosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2- il] -N-methylmethanesulfonamide in form of a colorless solid.

Example 3 N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-iso-propylpyrimidin-2-yl] -N-methylmethanesulfonamide

They were previously placed in 8 ml of toluene 512 mg (1.45 millimoles) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidin-5-yl] methanol and mixed with 96 mg (2.20 mmol) of sodium hydride (55% dispersion in mineral oil). After 1 h they were added to ambient temperature under vigorous stirring for 5 min 333.5 mg (1.44 mmol) of chlorodiphenylphosphine in 2.5 ml of toluene It was mixed with 28.7 mg (0.19 mmol) of iodide sodium and heated for 22 h to 108 ° C. After 6 h it mixed with another 28.7 mg (0.19 millimoles) of sodium iodide. After cooling to room temperature was mixed with 30 ml of sodium hydrogen sulphite solution at 38-40% and extracted with 50 ml of ethyl acetate. The organic phase was separated and the aqueous phase was extracted with 50 ml of ethyl acetate. The phases were then concentrated in vacuo Organic gathered. 740 mg of crude product were obtained, which by chromatography on silica gel (eluent: acetate ethyl) were purified and 212.7 mg (27.3%) of N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide in the form of a colorless solid.

Example 4 N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-iso-propylpyrimidin-2-yl] -N-methylmethanesulfonamide

They were placed in 8 ml of xylene (mixture of isomers) 502.6 mg (1.42 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidin-5-yl] methanol and mixed with 96.6 mg (2.21 mmol) of sodium hydride (55% dispersion in mineral oil). After 1 h they were added to room temperature, under vigorous stirring and for 5 min, 340.8 mg (1.47 mmol) of chlorodiphenyl phosphine in 2.5 ml of xylene. They were mixed with 34.6 mg (0.23 mmol) of sodium iodide and heated for 19 h to 136 ° C. After 3 h mixed with another 25.1 mg of sodium iodide. After cooling until room temperature was mixed with 30 ml of solution diluted sodium hydrogen sulphite and extracted with 50 ml of ethyl acetate. The organic phase was separated and the phase Aqueous was extracted with 50 ml of ethyl acetate. Then you concentrated the combined organic phases in vacuo. They were obtained 906 mg of crude product, which was purified by chromatography on silica gel (eluent: ethyl acetate), and 315.9 mg were isolated (41.3%) of N- [5- (diphenyl-phosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide in the form of a colorless solid.

Example 5 (reaction direct)

N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-iso-propylpyrimidin-2-yl] -N-methylmethanesulfonamide

They were placed in 7 g of low toluene 1.05 g (2.95 mmol) ice bath cooling [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl] methanol and mixed under stirring with 820 mg (3.69 mmol) of chlorodiphenylphosphine It was heated for 3 h at 108 ° C. After cool to room temperature, mixed with 553 mg (4.43 millimoles) of aqueous lye from potash (45%) and 97.5 mg (0.29 millimoles) of tetrabutylammonium bromide and stirred strongly for 1 h at 60 ° C. The heat source was removed and the mixture of reaction, still hot, was mixed with 20 ml of water. Left cool slowly to 4 ° C and the solid was filtered off precipitate. The product was washed with cold water and toluene and was dried under vacuum at 40 ° C. 1.04 g (64.1%; content: 97.6%) of N- [5- (diphenylphosphinoyl-methyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methyl-methanesulfonamide in the form of a colorless solid.

Example 6 (reaction direct)

N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-iso-propylpyrimidin-2-yl] -N-methylmethanesulfonamide

2.03 g (5.69 were placed in 13 g of toluene) millimoles) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl] methanol and under ice bath cooling they were mixed with 1.67 g (7.51 mmol) of chlorodiphenylphosphine in 2 g of toluene. I know heated for 2.5 h to 111 ° C. After cooling to room temperature was mixed with 1.08 g (8.66 mmol) of a 45% potash bleach and 175 mg (0.574 mmol) of tetrabutylammonium and stirred strongly for 2 h at 60 ° C. To Hot reaction mixture was added 30 ml of water. It stirred briefly at 60 ° C, slowly cooled to 4 ° C and separated by filtration the precipitated solid. The product was washed with cold water (10 ml) and cold toluene (10 ml) and dried under vacuum at 40 ° C. I know isolated 2.66 g (84.1%; content: 96.6%) of N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide in the form of a colorless solid.

Example 7 (reaction direct)

N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-iso-propylpyrimidin-2-yl] -N-methylmethanesulfonamide

2.02 g (5.69 were placed in 13.1 g of toluene) millimoles) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) -pyrimidin-5-yl] methanol and under ice bath cooling they were mixed with 1.67 g (7.51 millimoles) of chlorodiphenylphosphine in 1.9 g of toluene. It got hot for 3 h at 109 ° C. After cooling to temperature ambient, mixed with 590 mg (8.94 mmol) of hydroxide solid potassium and 159 mg (0.582 mmol) of 18-crown-6 and stirred heavily for 3.5 h at 60 ° C. To the hot reaction mixture were added 30 ml of water It was stirred briefly at 60 ° C, cooled slowly to 4 ° C and the precipitated solid was filtered off. The product was washed with cold water (10 ml) and with cold toluene (10 ml) and dried under vacuum at 40 ° C. 1.82 g (59.5%; content: 95.9%) of [N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide in the form of a colorless solid.

Example 8 (reaction direct)

N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-iso-propylpyrimidin-2-yl] -N-methylmethanesulfonamide

2.05 g (5.69 were placed in 13.1 g of toluene) millimoles) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) -pyrimidin-5-yl] methanol, and under ice bath cooling they were mixed with 1.71 g (7.69 mmol) of chlorodiphenylphosphine in 1.9 g of toluene. I know heated for 2.5 h to 111 ° C. After cooling to room temperature was mixed with 1.17 g (8.78 mmol) of bleach 30% soda and 182 mg (0.597 mmol) of chloride tetrabutylammonium and stirred vigorously for 3.5 h at 60 ° C. To Hot reaction mixture was added 30 ml of water. It stirred briefly at 60 ° C, slowly cooled to 4 ° C and separated by filtration the precipitated solid. The product was washed with cold water (10 ml) and cold toluene (10 ml) and dried under vacuum at 40 ° C. I know isolated 2.18 g (71.3%; content: 97.3%) of [N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropyl-pyrimidin-2-yl] -N-methylmethanesulfonamide in the form of a colorless solid (Melting Point 184-185 ° C).

Example 9 (reaction direct)

N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-iso-propylpyrimidin-2-yl] -N-methylmethanesulfonamide

A suspension of 9.29 g (26.3 mmol) of of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino)  pyrimidin-5-yl] methanol in 26 g of toluene was mixed under ice bath cooling with 7.64 g (34.4 mmol) of chlorodiphenylphosphine. He washed with a little toluene and heated for 2 h to 111 ° C. After cooling until room temperature was mixed with 4.94 g of a bleach of 45% potash and 873 mg (2.71 mmol) of bromide tetrabutylammonium and stirred strongly for 1 h at 60 ° C. To Hot reaction mixture was added 100 ml of water. It stirred briefly at 60 ° C, allowed to cool slowly to 4 ° C and separated by filtration the precipitated solid. The product was washed with water cold (30 ml) and cold toluene (30 ml) and dried under vacuum at 40 ° C. I know isolated 11.74 g (78.4%; content: 94.4%) of N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide in the form of a colorless solid.

Example 10 (direct reaction without catalyst transfer of phases)

N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-iso-propylpyrimidin-2-yl] -N-methylmethanesulfonamide

2.03 g (5.69 were placed in 13 g of toluene) millimoles) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) -pyrimidin-5-yl] methanol, and under ice bath cooling they were mixed with 1.69 g (7.60 millimoles) of chlorodiphenylphosphine in 1.9 g of toluene. It got hot for 2.5 h at 109 ° C. After cooling to temperature ambient was mixed with 1.09 g (8.74 mmol) of potash bleach at 45% and stirred vigorously for 2 h 45 minutes at 60 ° C. To Hot reaction mixture was added 30 ml of water. It stirred briefly at 60 ° C, slowly cooled to 4 ° C and separated by filtration the precipitated solid. The product was washed with cold water (10 ml) and cold toluene (10 ml) and dried under vacuum at 40 ° C. I know isolated 2.44 g (76.8%; content: 99.1%) of [N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide in the form of a colorless solid.

Example 11 (reaction direct)

N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-iso-propylpyrimidin-2-yl] -N-methylmethanesulfonamide

A solution of 60.08 g (0.173 mol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl] methanol in approximately 485 ml of toluene was mixed at 60 ° C with 42.55 g (0.192 moles; content: 99.7%) of chlorodiphenylphosphine. It stirred for 2.5 hours and this solution was added to a mixture, hot at 60 ° C, based on 70.66 g of potash bleach (20%) and 5.04 g (0.017 mol) of tetrabutylammonium chloride, and washed at then with 13 ml of toluene. It was stirred for 2 h at 60 ° C and was they added 215 ml of water and 108 ml of toluene. About 80 ° C the aqueous phase was separated and the organic phase was still extracted twice with 215 ml of hot water each time. He became dehydrated by azeotroped in the water separator and allowed to cool for 2 h up to 0 ° C. The precipitated crystals were filtered off and they were washed twice with 160 ml of toluene. After drying under vacuum at 40 ° C 81.94 g (89.7%) of N- [5- (diphenyl-phosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide in the form of a colorless solid [content (according to HPLC): 100%].

Claims (10)

1. Procedure for the preparation of N- [5- (diphenyl-phosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide of the formula 3 characterized in that [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl] methanol of the formula is reacted 4 with chlorodiphenylphosphine 2. Method according to claim 1, characterized in that the [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl] methanol of formula II is made react directly with chlorodiphenylphosphine and then with a base. 3. Method according to claim 1, characterized in that the [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl] methanol of formula II is first Deprotonize. 4. Method according to claim 3, characterized in that the deprotonization is carried out with an alkali metal hydride or an alkaline hexaalkyldisilazane. 5. Method according to claim 3 or 4, characterized in that the reaction is carried out with the aid of a catalyst. Method according to claim 5, characterized in that iodine, an alkaline iodide, an alkyl halide or a dihalogenated alkane are used as catalyst. Method according to one of claims 3 to 6, characterized in that the reaction with chlorodiphenylphosphine is carried out at a temperature between 80 ° C and 200 ° C. Method according to claim 2, characterized in that the direct reaction with chlorodiphenylphosphine is carried out at a temperature between -20 ° C and 130 ° C. 9. Method according to claim 2 or 8, characterized in that an alkali hydroxide is used as the base. Method according to claim 2, 8 or 9, characterized in that the reaction is carried out with the aid of a phase transfer catalyst.